Our long-term goals are to elucidate the role of hormonal (insulin/IGF-1) signaling in the control of aging and longevity in mammals and to determine how nutritional intake interacts with longevity genes. We have shown that caloric restriction (CR) increases longevity in the Ames dwarf mouse, a long-lived hypopituitary mutant, but surprisingly fails to extend longevity in another long-lived mutant, the growth hormone (GH) resistant, GH receptor knockout (GHRKO) mouse. Sensitivity to injected insulin was improved by CR in normal and in Ames dwarf mice but not in GHRKO animals. We hypothesize that failure of CR to prolong life in GHRKO mice is due to extremely low insulin levels and the inability of CR to further increase insulin sensitivity in these animals. We further hypothesize that stress resistance is related to insulin sensitivity and that CR will fail to improve stress resistance in GHRKO mice. These hypotheses will be tested by determining whether pancreatic islet-specific expression of IGF-1 that was shown to improve glucose tolerance and insulin secretion or replacement therapy with IGF-1 or insulin will normalize responses to short-term CR in GHRKO mice. Effects of these treatments will be assessed by measuring insulin and glucose tolerance, expression of insulin-related genes in the liver, skeletal muscle and heart (the "molecular signature" of responses to CR), resistance of cultured skin fibroblasts and intact mice to various stressors, measurements of body core temperature (Tco) and study of other parameters related to insulin action and stress resistance. Subsequently, we will use therapy that most closely "normalizes" the responses to short- term CR in GHRKO mice to determine whether it will also result in GHRKO mice regaining the ability to respond to chronic CR by increasing longevity. We will also examine effects of CR in the recently developed Ghrh-KO mice with isolated GH deficiency and in transgenic mice expressing GH antagonist. Collectively, these studies will identify the effects of CR on insulin signaling and stress resistance that are consistently associated with prolonged longevity across a variety of genotypes. The results will provide novel insights into the mechanisms of anti-aging actions of CR and into the relationship of insulin level and actions to stress resistance, aging and longevity, an issue of major significance in public health in the context of the current "epidemic" of insulin resistance and metabolic syndrome.